Regarding the research report entitled "Severe Dopaminergic Neurotoxicity
in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy")",
published in Science in September of 2002:

The authors (Ricaurte et al)
casually refer to a case report as an example of "MDMA-induced
Parkinsonism." The patient in question was a young man who had reported
infrequent use of the drug (a total of ten exposures) over the course of the
past year.[1] He had not used "ecstasy" for approximately
three months when he presented for the symptom of "slight clumsiness in
upper and lower extremities." Over several months following initial presentation
for treatment, his condition rapidly worsened, developing more features characteristic
of
Parkinson's. The patient did not respond to "the maximal tolerated doses
of levodopa and pramipexole", leaving the fundamental assumption of damage
to the dopaminergic system as the source of the patient's problems very much
in doubt.

The doctors who reported this
case state that "we have
no firm evidence of a causal relation between this patient's drug use and
his parkinsonism";
their belief that it may have been caused by infrequent MDMA use seems
to be born almost entirely of their inability to make an alternative diagnosis
coupled
with MDMA's known dopaminergic neurotoxic potential in mice.

The pathology
of this case (delayed onset relative to drug use followed by rapid progression)
is inconsistent with all known research on the progression
of MDMA
neurotoxicity, which produces a maximization of damage shortly after exposure
followed by slow partial recovery.[2]

If Ricaurte et al have additional
information about this case that was unavailable to the doctors treating
the patient,
they have made no mention
of it. At
the least, it was dishonest to characterize this case simply as an example
of "MDMA-induced
Parkinsonism" with no mention of the extraordinarily tenuous and speculative
nature of the proposed causal link between the patient's drug use and his
neurological symptoms.

Equally intriguing is the author's
claim that "oral
administration offers little or no significant neuroprotection" relative
to the injected route used in the experiment. Indeed, Ricaurte's own research
has demonstrated that
injecting MDMA can double and even triple it's neurotoxicity (depending
on brain region) vs. oral dosing.[3] While I will concede that "little
or no" is
not a clearly defined expression, increases of whole multiples seems to
strain any common definition.

Indeed, the very title of the
report is rather difficult to defend, as it describes the dose used as "a
common recreational dose" of MDMA.
If the dose was pharmacologically equivalent to doses routinely
taken by humans, why do
the authors report that 20% of their animals died on the spot, while an
additional 20% may have died had they not been exempted from the full regimen
after
showing serious distress from only part of the total 6 mg/kg dose? While
dosages of
such scale do (infrequently) occur in human users, it is likely that these
users have
reached such dosages in response to growing drug tolerance; with such progressive
elevations of dosage over time, neurotoxic potential is reduced.[4] It
seems unlikely to me that a man of Ricaurte's standing within the field
of MDMA
neurotoxicity
was unaware of this, yet no mention of this confound is made in the author's
rush
to claim equivalency between their experiment and human
patterns of use.

The authors report that 6
mg/kg of MDMA total (2 mg/kg every two hours for 3x) produced profound
(approx. 50%) damage
to the
dopaminergic system in monkeys, but fail to explain why Ricaurte's own
past work has found that a cumulative dose of 40 mg/kg (5 mg/kg at a time
2x for
four days)
failed to produce any dopaminergic toxicity in monkeys.[5] At the very
least, producing a vast increase in toxicity by giving 2 mg/kg 3x instead
of a
single 5 mg/kg
dose seems to demand some discussion; it suggests that at the least the
authors have managed to come upon an atypically toxic dosing regimen.
If only on the
grounds of the sheer novelty of the results from this particular dosage
regimen it seems presumptuous to declare equivalency to human users until
some explanation
can be offered for the sharp divergence of results between these two experiments.

Also of no small concern in
the author's suggestions of severe dopaminergic toxicity commonly occurring
in humans is their apparent refusal
to mention
retrospective
studies of the brains of "ecstasy" users that found no differences
in their dopamine system relative to non-users.[6][7] While the latter
study may not have yet been available to the authors at the time of publication,
surely
they should have mentioned that there was existing evidence of the absence
of harm to user's dopamine systems before publishing a paper that so shamelessly
encourages public panic.

The principle author (Ricaurte)
has long championed a minimalistic method of interspecies dosage scaling
between non-human primates and humans.
His
understanding
of MDMA neurotoxicity has led him to believe that less than 1.3 mg/kg of
MDMA in a human user would produce neurotoxic damage (a dose he arrived
at by scaling
from 5 mg/kg in non-human primates, which he reports as producing neurotoxicity.)[8] If
we believe Ricaurte's claims of dosage scaling between humans and non-human
primates, then the 6 mg/kg dose used in his recent experiment (which killed
a significant number of his animals and severely damaged the serotonergic
and dopaminergic
pathways in the survivors) would be equivalent to just over 1.5 mg/kg in
humans. However, prospective human brain-scan experiments have failed to
find even the
slightest indication of neurotoxicity (or even subject distress) at 1.5
mg/kg.[9] Human users routinely exceed this dosage, mix
drugs, and use under uncontrolled
and adverse conditions, yet fatalities are rare. Indeed, examinations of
the brains of current human "ecstasy" users
with an average lifetime exposure of ~800 tablets found only minor
reductions in SERT (serotonin transporter) density, and when abstinent
users were examined,
their regional and total SERT densities were indistinguishable from non-drug
users.[10] While regrowth of serotonin axons could explain a recovery of
total SERT density, the recovery seen in these heavy human users was uniform,
precisely
restoring normal SERT density in all regions of the brain studied, as contrasted
with the patterns of serotonin axon regrowth seen in non-human primates
given neurotoxic doses of MDMA (which produced hyperenervation of regions
near the
raphe nuclei but failed to restore enervation to less proximal regions.)
Given this
pattern of recovery, there is every reason to believe that the minor
temporary loss of available SERT proteins observed was not due to neurotoxic
damage (destruction of
axons.)

Ricaurte also fails to explain
why his "common [human]
recreational dose" of
MDMA produced a significant and prolonged (even lethal) hyperthermic
response (as much as 41.6C) when human experiments have consistently produced
little
or
no hyperthermic
response
at any dose attempted.[11][12] As hyperthermic response
is well-established as a critical factor in MDMA neurotoxicity[13], I
must again question why
Ricaurte believes
the dosages he uses are pharmacologically equivalent to those used by
humans when the physiological responses produced are not equivalent. It's
certainly true that
malignant
hyperthermia appears with some frequency among human users, but such
cases are usually associated with prolonged dancing at clubs. Are we
to
believe that Ricaurte
et al. threw a 'rave party' for their animals?

In
the final analysis, I must regard this recent product of Ricaurte et al.
as more of an act of propaganda than a sincere attempt to advance public
understanding. There is no reason to believe that there is a coming wave
of 'Ecstasy Parkinsonism'
among human "ecstasy" users, or even that common patterns of
use pose a risk of injury to the dopaminergic system. Shame on the authors
for the incomplete, misleading and sensationalistic nature
of this
research
report,
and shame
on the editors
of Science for publishing it.